Recent studies indicated the involvement of selectin-oligosaccharide interactions in various inflammatory disease. It is known that E-selectin (ELAM-1), P-selectin (GMP-140) or L-selectin (LECAM-1) plays an important role in the migration of inflammatory cells from the blood stream to inflammatory sites. These selectin family are expressed on a variety of cell surfaces. For example, ELAM-1 is an adhesion molecule on vascular endothelial cells with inflammation. GMP-140 is an adhesion molecule expressed on platelets or vascular endothelial cells. LECAM-1 is an adhesion molecule expressed on leukocytes. These selectins are believed to be involved in a complicated manner in the progress of clinical manifestation of complicated a disease such as chronic inflammation. Attempts have been made, therefore, to find a blocker of selectins effective to inhibit their cell-adhesion activities at an early stage of inflammation. To this end, it would be desirable for the blocker to exert its cell adhesion-inhibitory effects on all members of the selectin family.
It has also been reported that various selectins are involved in ischemia-reperfusion injury accompanying invasion of neutrophils into endothelium. Buerke et al., J. Clin. Invest., 93, 1140-1148 (1994); and Okada et al., Stroke, 25, 202-210 (1994). It has also been reported that antibodies to E-selectin, P-selectin and L-selectin, respectively, attenuated ischemia-reperfusion injury in the model animals. D. Altavill et al., Eur. J. Pharmacol., 270, 45-51 (1994); R. K. Winn et al., J. Clin. Invest., 92, 2042-2047 (1993); and Xin-liang Ma et al., Circulation, 88, 649-658 (1993). Y. Seko et al. reported in Pro. Jpn. Soc. Immunol., 24, 108 (1994) a synthetic selectin oligopeptide effective in the reduction of rat myocardial ischemia-reperfusion injury. It is, therefore, believed that a blocker for cell adhesion activities of selectins is also useful in controlling ischemia-reperfusion injury.
M. L. Phillips et al. reported in Science, 250, 1130-1132 (1990) that the native ligand for ELAM-1 is sialyl Lewis.sup.x oligosaccharide. Since then a certain number of its derivatives have been reported. See, U.S. Pat. No. 5,143,712; U.S. Pat. No. 5,211,936; U.S. Pat. No. 5,211,937; U.S. Pat. No. 5,369,096; and EP-A-589556. These derivatives reported as ligands binding to ELAM-1 are oligosaccharides bearing fucose and sialic acid or a long chain alkanoic moiety in the molecule.
The present invention provides a novel glycolipid derivative which binds to any of the selectins as a ligand. The invention also provides a pharmaceutical composition for use in the prophylaxis or treatment of various inflammatory disease or reperfusion injury after ischemia comprising a pharmaceutically acceptable salt of said glycolipid derivative.